US 12,215,080 B2
Hydrazinyl-pyrrolo compounds and methods for producing a conjugate
David Rabuka, Kensington, CA (US); Aaron Edward Albers, San Francisco, CA (US); Romas Alvydas Kudirka, Berkeley, CA (US); Albert W. Garofalo, South San Francisco, CA (US); and Jesse M. McFarland, Berkeley, CA (US)
Assigned to Redwood Bioscience, Inc., Emeryville, CA (US)
Filed by Redwood Bioscience Inc., Emeryville, CA (US)
Filed on Oct. 8, 2021, as Appl. No. 17/497,735.
Application 16/435,221 is a division of application No. 15/276,479, filed on Sep. 26, 2016, granted, now 10,464,894, issued on Nov. 5, 2019.
Application 15/276,479 is a division of application No. 14/555,283, filed on Nov. 26, 2014, granted, now 9,493,413, issued on Nov. 15, 2016.
Application 17/497,735 is a continuation of application No. 16/723,417, filed on Dec. 20, 2019, granted, now 11,180,451.
Application 16/723,417 is a continuation of application No. 16/435,221, filed on Jun. 7, 2019, granted, now 10,604,483, issued on Mar. 31, 2020.
Claims priority of provisional application 61/909,897, filed on Nov. 27, 2013.
Prior Publication US 2022/0153696 A1, May 19, 2022
Int. Cl. C07D 209/14 (2006.01); A61K 47/68 (2017.01); C07D 405/12 (2006.01); C07D 498/18 (2006.01)
CPC C07D 209/14 (2013.01) [A61K 47/68031 (2023.08); A61K 47/68033 (2023.08); A61K 47/6809 (2017.08); A61K 47/6811 (2017.08); A61K 47/6889 (2017.08); C07D 405/12 (2013.01); C07D 498/18 (2013.01)] 21 Claims
 
1. A conjugate of formula (IIIa):

OG Complex Work Unit Chemistry
wherein:
m is 0 or 1;
R1 is selected from hydrogen and alkyl;
R2 and R3 are each alkyl;
X1 is C or N, wherein if X1 is N, then Y1 is absent;
X2, X3 and X4 are each C;
Y1, if present, Y2, Y3 and Y4 are each hydrogen;
L is a linker represented by -(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-, wherein a, b and c are each 1, and d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 3 to 5;
wherein T1, T2, T3, T4 and T5 and V1, V2, V3, V4 and V5 are selected from the following table:
 
T1 V1 T2 V2 T3
 
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CONR11— (PEG)n —CO— (EDA)w
(C1-C12)alkylene —CO— (EDA)w —CO— (CR13OH)h
(C1-C12)alkylene —CO— (AA)p —NR11— (C1-C12)
 
 
 
 
 alkylene
(C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p
(C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p
(C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p
(C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p
(C1-C12)alkylene —CO— (EDA)w —CO— (CR13OH)h
(C1-C12)alkylene —CO— (AA)p —NR11— (C1-C12)
 
 
 
 
 alkylene
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CO— (AA)p —NR11— (C1-C12)
 
 
 
 
 alkylene
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p
(C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p
(C1-C12)alkylene —CO— (EDA)w —CO— (CR13OH)h
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CONR11— (PEG)n —CO— MABO
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CO— (AA)p —NR11— (PEG)n
(C1-C12)alkylene —CONR11— (PEG)n —CO— MABC
(C1-C12)alkylene —CONR11— substituted —NR11— (PEG)n
 
 
 (C1-C12)
 
 
 
 
 alkylene
 
 
(C1-C12)alkylene —CONR11— (PEG)n —CO— (AA)p
(C1-C12)alkylene —CONR11— (C1-C12) — (CR13OH)h
 
 
 alkylene
 
 
(C1-C12)alkylene —CO— P4A —CO— (C1-C12)
 
 
 
 
 alkylene
(C1-C12)alkylene —CO— P4A —CO— (C1-C12)
 
 
 
 
 alkylene
(C1-C12)alkylene —CO— P4A —CO— (C1-C12)
 
 
 
 
 alkylene
(C1-C12)alkylene —CO— P4A —CO— (C1-C12)
 
 
 
 
 alkylene
 
V3 T4 V4 T5 V5
 
—CO— — — — —
—NR11— — — — —
— — — — —
—CONR11— (C1-C12)alkylene —CO— — —
—CO— — — — —
— — — — —
— MABO — — —
— PABO — — —
— PABC — — —
—CO— (AA)p — — —
—CO— (AA)p — — —
—CO— (AA)p — — —
—CO— (AA)p — — —
—CO— (AA)p— — — —
 
 PABC—
 
 
 
 
 (AA)p
 
 
 
—CO— (AA)p— — PABC— —
 
 
 
 (AA)p
 
—CO— (AA)p— — — —
 
 PABO
 
 
 
—CO— (AA)p — PABO —
—SO2— (AA)p — — —
— PABC— — — —
 
 (AA)p
 
 
 
— PABC — — —
—CONR11— (PEG)n —CO— — —
—CO— MABC— — — —
 
 (AA)p—
 
 
 
—CO— MABC — (AA)p —
— — — — —
—CO— MABO — — —
—CO— PABO — — —
—CO— PABC — — —
— (AA)p — — —
—CO— — — — —
— PABC — —NR11— —
—CONR11— — — — —
—CO— (AA)p — PABO —CO—
—CO— (AA)p — PABO —
—CO— (AA)p — PABC  —
 
 
 
 (AA)p
 
—CO— (AA)p— — — —
 
wherein:
EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue;
piperidin-4-amino (P4A) is

OG Complex Work Unit Chemistry
MABC is

OG Complex Work Unit Chemistry
MABO is

OG Complex Work Unit Chemistry
PABC is

OG Complex Work Unit Chemistry
PABO is

OG Complex Work Unit Chemistry
w is an integer from 1 to 20;
n is an integer from 1 to 30;
p is an integer from 1 to 20;
h is an integer from 1 to 12;
R11 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
R13 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
each R14 is independently selected from hydrogen, alkyl, substituted alkyl, a polyethylene glycol moiety, aryl, and substituted aryl;
each R15 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
each R16 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
W1 is a drug; and
W2 is an antibody.